Process for making anesthetic bases and intermediates



Patented Aug. 12, 1941 UNHTE 2|":

STATES PET FICE

PROCESS Samuel D. Goldberg,

FOR MAKING ANESTHETIC BASES AND INTERMEDIATES Forest Hills, N. Y.,assignor No Drawing.

Application June 15, 1938,

Serial No. 213,931

5 Claims.

This invention relates to processes for menufa'cturing local anestheticbases and solutions and intermediates therefor. This application is acontinuation in part of my copending application Ser. No. 43,713, filedOctober 5, 1935, now Patent No. 2,139,818.

The principal object of the present invention is to provide a simple andefhcient process for the production of anesthetic bases and solutions;and to provide a method for producing intermediates for the manufactureof such bases.

In my said copending application there are olescribed a series of localanesthetic bases and solutions having relatively low toxicity comparedwith their potency, which may employ a smaller quantity of anestheticand vaso-constrictor to produce equal or greater anesthetic effects; aswell as a series of local anesthetic bases in solutions which may beused as surface anesthetic requiring less than the quantity of procainefor this purpose and having other advantages; and methods for producingthese materials.

According to the present invention, I have found a process for producingan anesthetic base comprising combining a nitro benzoyl compound with acompound comprising a substituted secondary amino ethanol to form a monoalkyl amino ethyl nitro benzoate, and reducing the resulting compound toform a mono alkyl amino ethyl amino benzoate. In accordance with myinvention, I have also found a process for producing said ethanols.

An example of the process embodying my invention will now be describedas follows:

Example 1 A mono alkyl amino ethanol prepared as described below isreacted with a nitro benz'oyl halide to produce the corresponding monoalkyl amino ethyl nitro benzoate which is then reduced to form a monoalkyl amino ethyl amino benzo'ate as described in my said copendingapplication Serial No. 13,713, now Patent No. 2,139,818. A method whichI have successfully employed for the production of the ethanol is asfollows:

Into a pressure flask is placed 149 grams of normal mono butyl anilineto which is added directly 40 grams (or .95 mol) of ethylene oxide. Theflask was immediately stoppered and well shaken. It was then allowed tostand at room temperature for about three weeks. At the end of this timethe contents of the flask were transferred to a distilling flask anddistilled. The

yield of butyl hydroxy ethyl aniline was quantitative. There was no lowboiling fraction. The yield was 155 grams or 96% of theory. Boilingpoint 800 at 760 millimeters. To 50 grams (1 mol) of butyl hydroxy ethylaniline thus prapared was added 19 grams of hydrochloric acid (2 mols)and the mixture cooled to 5 C. While agitated 1 mol of sodium nitritewas added slowly until the test with starch iodide paper indicated aslight excess of nitrous oxide. The nitrosated material was then droppedslowly on a boiling solu-- tion of 50% sodium hydroxide andsteam-distilled. The steam distillation was continued until thedistillate was no longer cloudy. The distillate was then extracted withether, the ether dried and distilled. The yield was 10 grams of thenormal mono butyl amino ethanol boiling at 198 to 200 or 33 theory.

This method may be employed for preparing the other mono alkyl secondaryalcohols, namely the mono-iscbutyl-, the mono-normal-amyl-, andmono-is0amyl-, mono-normal-propylg the monoisopropy1-, and themono-ethyl-amino ethanol.

The normal butyl ethanol and the other ethanols just recited are reactedwith a nitro benzoyl halide, for instance, with para nitro benzoylchloride to form the corresponding normal alkyl amino ethyl nitrobenzoates, which are then reduced to form the corresponding mono alkylamino ethyl amino benzoates. As pointed out above, the formation of thenitro benzoates and their reduction, including the precautions to beobserved, are more fully set forth in my said Patent No. 2,139,818.

Another reaction which may be employed is that between para nitrobenzoyl chloride and ethylene chlorhydrin to produce chlor ethyl paranitro benzoate which may be reduced to produce chlor ethyl para aminobenzoate. This may then be reacted with an alkyl primary amine to formthe mono alkyl amino ethyl para amino benzoate. The reaction is asfollows:

OHCHzCHzCl chlor ethyl para nitro benzoate. Reduce nitro ethylenechlorgroup to amine hydrin group. N 0 N 02 OOOCHZOHZCI COOCHZCHzNHR +H0lchlor ethyl +NH2R mono alkyl para amino ethyl amino ethyl benzoateprimary para amino amine bonzoate N H: N Hz Example 2 Specifically theprocess may be carried out as follows: 25 grams of para nitro benzoylchloride and grams of anhydrous ethylene chlorhydrin in cc. of benzenewere refluxed until hydrochloric acid gas was no longer evolved. Thebenzene solvent was then removed by filtration and the residue washedwith a 10% solution of sodium hydroxide which removed the unreacted paranitro benzoyl chloride and some para nitro benzoic acid which had beenformed, and then washed with water until free from alkali and air dried.It was recrystallized from alcohol and ob tained in the form of longyellow needles with a melting point of 56 C. The yield was practicallytheoretical.

The chlorethyl para nitro benzoate was re duced with the aid of tin andhydrochloric acid in an alcoholic solution as follows: 50 grams ofchlorethyl para nitro benzoate, 60 grams of tin, 200 cc. of concentratedhydrochloric acid in 200 cc. of ethyl alcohol were allowed to react inthe usual manner. When the reaction was completed, the solution wascooled until the entire mass became solid, and then transferred to asuction funnel and washed sparingly with ethyl alcohol. It was thentransferred to a beaker, where the solid compound was treated with a 20%sodium hydroxide solution. The tin dissolves, and the granules whichwere formed on standing, were then filtered oil, washed with water untilfree from alkali and dried. In order to free these granules from the tinwhich they enclosed, the solid material was extracted with acetone andfiltered with the aid of filter cell. The acetone solution was thendistilled oil and a 50% solution of alcohol and water added to theresidue to recrystallize the chlorethyl para amino benzoate. The crystalformed were long pale yellow needles, melting at 84.5 C. and the yieldwas grams or 80% of theory.

10 grams of chlorethyl para amino benzoate, and 4 grams of isobutylamine in grams of amyl alcohol were allowed to reflux for twentyfourhours, the alcohol was then distilled and the residue extracted with adilute solution of hydrochloric acid. It was then filtered from anyinsoluble materials and the clear solution reprecipitated with ammonia.The oil that was formed was extracted with ether and dried. The oil ismono isobutyl amino ethyl para amino benzoate. The hydro chloride ofthis compound is prepared therefrom by adding the necessary quantity ofhydrochloric acid. It is then recrystallized from a suitable solventfrom which it is crystallized.

Example 3 Instead of conducting the reaction of nitro benzoyl chloridewith anhydrous ethylene chlorhydrin in benzene, it may be conducted inalkaline solution for example in sodium hydroxide solution, and thechlor ethyl para nitro benzoate thereafter transformed into theanesthetic. Specifically this is done as follows:

10 grams of anhydrous chlorohy-drin are added to 100 cc. of water inwhich is placed 3 grams of solid sodium hydroxide. The reaction mixtureis stirred with cooling until the sodium hydroxide goes into solution.The temperature is then raised by external heat to between 30 and 40 C.Then 25 grams of powdered para nitro benzoyl chloride is added, thereaction mixture stirred when a rise in temperature will be obtained andan oil is first formed. On further agitation and cooling chlor ethylpara nitro benzoate which is formed becomes a solid. The chlor ethylpara nitro benzoate is reduced as indicated in Example 1 and reactedwith the primary amine to form the mono alkyl ethyl para amino benzoate.

The methods may be employed for preparing other mono alkyl anesthetics,for example the mono-normal butyl-, mono-normal-amyland mono isoamyl-,mono normal propyl-, and mono-isopropyl-, and mono-ethyl-amino ethylamino benzoates.

The expression mono butyl amino as employed in the claims is intended tocover both mono normal butyl amino compounds as well as compoundscontaining the isomers of the mono butyl group, Similarly the expressinsmono amyl amino and mono propyl amino are intended to cover both thenormal compounds and the isomers thereof.

While I have described my improvements in great detail and with respectto preferred forms thereof, I do not desire to be limited to suchdetails and forms since many changes and modifications may be made andthe invention embodied in Widely different forms without departing fromthe spirit and. scope thereof in its broader aspects. Hence I desire tocover all modifications, forms and embodiments coming within thelanguage or scope of any one or more of the appended claims.

What I claim as new and desire to secure by Letters Patent is:

1. A process for the preparation of an ethanol which comprises reactinga mono alkyl aniline with ethylene oxide to obtain the correspondingalkyl hydroxy ethyl aniline, nitrosating the alkyl hydroxy ethylaniline, and treating the nitrosated material with caustic alkali toform mono alkyl amino ethanol.

2. A process for producing an anesthetic base which comprises reacting amono alkyl aniline with ethylene oxide to obtain the corresponding alkylhydroxy ethyl aniline, nitrosating the alkyl hydroxy ethyl aniline,treating the nitrosated material with caustic to form mono alkyl aminoethanol, combining a nitro benzoyl halide compound with said ethanol toform a mono alkyl amino ethyl nitro benzoate, and reducing the resultingcompound to form a mono alkyl amino ethyl amino benzoate.

3. A process according to claim 2 in which the mono alkyl aniline ismono butyl aniline and the benzoate .obtained is mono butyl amino ethylamino benzoate.

4. A process according to claim 2 in which the mono alkyl aniline ismono propyl aniline and the benzoate obtained is mono propyl amino ethylamino benzoate.

5. A process according to claim 2 in which the mono alkyl aniline ismono amyl aniline and the benzoate obtained is mono amyl amino ethylamino benzoate.

SAMUEL D. GOLDBERG.

'\ Patent No. 2,251,996. August 12, 19in.

CERTIFICATE OF CORRECTION.

\ SAMUEL D. GOLDBERG.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correctionas follows: Pagel,first column, line 19, for "anesthetic" read anesthetics-e; same page,second column, line 5, for "prepared" read -prepared-; line 18, before"theor y' insert --of; lines 51-514., in the reaction, for "ethylprimary amine" read alkyl primary amine--; page 2, first column, lines55 and 56, strike out I the words "from which it is crystallized" samepage second column, "line 22, for "expressins" read "expressions"; andthatthe said Letters Patent should be read with this correction thereinthat the same may conform to the record of the case in the Patent OfficeSigned and sealed this ll th day of October, A. D. 1914.1.

Henry Van Arsdale, (Sea1) Acting Commissioner of Patents.

